Drug substances are usually administered as part of a formulation in combination with one or more other agents that serve varied and specialized pharmaceutical functions. Dosage forms of various types may be made through selective use of pharmaceutical excipients. As pharmaceutical excipients have various functions and contribute to the pharmaceutical formulations in many different ways, e.g., solubilization, dilution, thickening, stabilization, preservation, coloring, flavoring, etc. The properties that are commonly considered when formulating an active drug substance include bioavailability, ease of manufacture, ease of administration, and stability of the dosage form. Due to the varying properties of the active drug substance to be formulated, dosage forms typically require pharmaceutical excipients that are uniquely tailored to the active drug substance in order to achieve advantageous physical and pharmaceutical properties.
Cyclopropane carboxylic acid {2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (“Compound A”) is a novel compound with anti-inflammatory activity in clinical development for the treatment of a variety of chronic inflammatory conditions. Pharmacologically, Compound A blocks the degradation of cyclic adenosine monophosphate (cAMP) via inhibition of the phosphodiesterase type IV (PDE4) enzyme, resulting in an increase in cAMP in PDE4-expressing cells including monocytes, T cells, and neutrophils. Enzyme assay data using purified PDE4 enzyme from U937 human monocytic cells indicate that Compound A has a PDE4 IC50 of 100 nM (50 ng/mL). Compound A and methods for its synthesis are described, e.g., in U.S. Patent Publication No. 2010/0129363, the disclosure of which is hereby incorporated by reference in its entirety. Compound A may also be prepared according to the process described in U.S. Patent Publication No. 2010/0168475, the disclosure of which is hereby incorporated in its entirety.
Due to its diversified pharmacological properties, Compound A is useful in treating, preventing, and/or managing various diseases or disorders. However, Compound A is poorly soluble, thus, a need exists as to dosage forms of Compound A having advantageous physical and pharmaceutical properties.
It has been demonstrated in monkeys that delivering an amorphous solid dispersion using a capsule gave approximately 3.5 times the exposure compared to the crystalline form. A tablet formulation can disintegrate quickly, increasing the timeline for absorption. Polymers can help maintain the supersaturation, further increasing the timeline for absorption. A tablet formulation with low friability may also help decrease chipping and loss of active pharmaceutical ingredient during film coating. See, e.g., Puri V., Dantuluri A. K. and Bansal A. K, “Investigation of Atypical Dissolution Behavior of an Encapsulated Amorphous Solid Dispersion,” Journal of Pharmaceutical Sciences (2011) 100(6):2460-8.